Opioid regulation of hypothalamic neurons

描述（由申请人提供）：阿片受体激动剂在产生镇痛方面非常有效，但其临床应用受到神经奖励回路激活导致的耐受性和高滥用倾向的发展的阻碍。因此，了解阿片类药物如何调节奖赏回路以及阿片受体信号传导如何随着阿片类药物暴露而变化是克服阿片类药物治疗目前临床局限性的关键步骤。释放和响应阿片类物质的一个重要奖赏途径包括下丘脑前阿黑皮素（POMC）神经元。最近的数据表明，POMC神经元受到阿片类药物作用于POMC神经元的调节，也受到阿片类药物作用于POMC神经元突触前末梢的调节。有趣的是，虽然POMC神经元上的突触后μ阿片受体在几分钟内经历脱敏，但介导抑制递质释放的突触前μ阿片受体不容易脱敏。本研究的目的是：1）确定突触前抵抗脱敏的机制; 2）确定突触前和突触后阿片受体调节差异的后果。这些目标将在脑切片中使用电生理学、光遗传学和成像方法来实现。这些结果可能会提供深入了解如何防止突触后受体脱敏，并将彻底定义阿片类药物如何通过突触前和突触后受体在急性和慢性暴露于阿片类药物期间影响奖励回路中的神经元活动。

DESCRIPTION (provided by applicant): Opioid receptor agonists are highly effective at producing analgesia, but their clinical use is hindered by the development of tolerance and high abuse liability resulting from activation of the neural reward circuitry. Therefore, understanding how opioids regulate reward circuits and how opioid receptor signaling changes with opioid exposure are key steps towards overcoming current clinical limitations of opioid therapy. One important reward pathway that releases and responds to opioids includes the hypothalamic proopiomelanocortin (POMC) neurons. Recent data show that POMC neurons are regulated by opioids acting on POMC neurons and also by opioids acting on terminals presynaptic to POMC neurons. Interestingly, while postsynaptic mu opioid receptors on POMC neurons undergo desensitization within minutes, presynaptic mu opioid receptors that mediate the inhibition of transmitter release do not readily desensitize. The goals of the present proposal are to 1) determine the mechanisms underlying the presynaptic resistance to desensitization and 2) to determine the consequence of differential pre- and postsynaptic opioid receptor regulation. These goals will be achieved using electrophysiologic, optogenetic and imaging approaches in brain slices. The results may provide insight into ways to prevent postsynaptic receptor desensitization and will thoroughly define how opioids affect neuron activity in a reward circuit via pre- and postsynaptic receptors during acute and chronic exposure to opioids.